title: A novel ALDH5A1 mutation is associated with succinic semialdehyde dehydrogenase deficiency and severe intellectual disability in an Iranian family.
abstract: Succinic semialdehyde dehydrogenase (SSADH) deficiency is a disorder of the catabolism of the neurotransmitter gamma-aminobutyric acid (GABA) with a very variable clinical phenotype ranging from mild intellectual disability to severe neurological defects. We report here on a large Iranian family with four affected patients presenting with severe intellectual disability, developmental delay and generalized tonic-clonic seizures. Molecular genetic analysis revealed a missense mutation c.901A>G (p.K301E, RefSeq number NM_001080) in ALDH5A1 co-segregating with the disease in the family. The missense mutation affects an amino acid residue that is highly conserved across the animal kingdom. Protein modeling showed that p.K301E most likely leads to a loss of NAD(+) binding and a predicted decrease in the free energy by 6.67 kcal/mol furthermore suggests a severe destabilization of the protein. In line with these in silico observations, no SSADH enzyme activity could be detected in patient lymphoblasts.
authors.affiliation: Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Lucia
authors.initials: L
authors.lastname: Püttmann
authors.forename: Henning
authors.initials: H
authors.lastname: Stehr
authors.forename: Masoud
authors.initials: M
authors.lastname: Garshasbi
authors.forename: Hao
authors.initials: H
authors.lastname: Hu
authors.forename: Kimia
authors.initials: K
authors.lastname: Kahrizi
authors.forename: Bettina
authors.initials: B
authors.lastname: Lipkowitz
authors.forename: Payman
authors.initials: P
authors.lastname: Jamali
authors.forename: Andreas
authors.initials: A
authors.lastname: Tzschach
authors.forename: Hossein
authors.initials: H
authors.lastname: Najmabadi
authors.forename: Hans-Hilger
authors.initials: HH
authors.lastname: Ropers
authors.forename: Luciana
authors.initials: L
authors.lastname: Musante
authors.forename: Andreas W
authors.initials: AW
authors.lastname: Kuss
mesh_terms: D050842:1-Pyrroline-5-Carboxylate Dehydrogenase / Q000235:genetics*; D000328:Adult; D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics*; D004247:DNA / Q000032:analysis / Q000235:genetics; D002658:Developmental Disabilities; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D007492:Iran; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D050644:Succinate-Semialdehyde Dehydrogenase / Q000097:blood / Q000172:deficiency / Q000235:genetics; D055815:Young Adult
chemical_list: D004247:DNA; C493643:ALDH5A1 protein, human; D050644:Succinate-Semialdehyde Dehydrogenase; D050842:1-Pyrroline-5-Carboxylate Dehydrogenase; C494240:ALDH4A1 protein, human
keywords: ALDH5A1; Iranian; SSADH deficiency; autosomal recessive; intellectual disability